William G. Wierda, MD, PhD: And what I'm hearing is today chemo/chemoimmunotherapy is pretty much a standard of care for first-line. When we move into the discussion about the small molecule inhibitors, perhaps not so much anymore is chemoimmunotherapy a relevant issue.

Susan M. O’Brien, MD: Exactly.

Richard R. Furman, MD: But I think just to follow up on something that Susan had said: it's important to keep in mind that no one will ever argue that MRD negativity is certainly better than MRD positivity. It's unclear whether doing something additionally that makes one MRD-negative quicker really provides an advantage. And so certainly, if we identify patients who might not be served by a long time to MRD negativity, people with genomic instability—and this is where the complex karyotype really becomes very helpful—those are the people who you might justify getting a deep remission quickly. But by and large, you know progression-free survival is really going to be what's most important to patients. And so, whether or not you get there quickly or slowly, it's really, in essence, how are you going to do long term? And that's just an important thing to always keep in mind.

Susan M. O’Brien, MD: I think it is. And obviously, most of the MRD data that we have is, or all of it, is based on chemoimmunotherapy. On the other hand I'm willing to go out on a limb and say, whatever your treatment is, if you don't become MRD-negative, I don't buy that you're going to be in remission 10 years later. I don't think it's going to happen.

Richard R. Furman, MD: But we need to figure out with the novel agents when that time point is. The important question is, how do we assess? So we really need to reinvestigate all the prognostic markers with the new agents and figure out who is that subset of patients that is not going to be served with a novel agent. So when you look at the PCYC-1102 treatment-naïve population, all but one of those patients is doing remarkably well. The question is when you look at the relapsed/refractory patients and the number of people doing well is less, so we're down to about a 70% progression-free survival at three years.

Richard R. Furman, MD: Single-agent ibrutinib. It's really about identifying who are those 30% of patients and what else we can really do to help them long term.

William G. Wierda, MD, PhD: I think the nice thing about considering MRD and having a discussion about it is that it's potentially an early endpoint that we can look at, without having to wait for PFS, in order to develop new and more effective therapies. It's great that we have all these new very, very active agents and they have extended out the PFS curves, as you know, remarkably. But that's a challenge also in terms of developing new treatments and making advances. Because if all of our progress is dependent on looking at that endpoint, it's going to slow things down for us in terms of development.

Richard R. Furman, MD: Absolutely.

William G. Wierda, MD, PhD: It would be nice to have something that's an early endpoint to look at that will tell us, yes, this is an effective or a more effective treatment. And then we can move from there. What are your thoughts, Tom, on MRD and where it's potentially useful in the community and in research investigations?

Thomas J. Kipps, MD, PhD: I think the absence of minimal residual disease is very important, in that it's probably the only way you're going to be able to say that you can potentially cure a patient if they have no evidence of active disease. The technique for assessing for minimal residual disease, which is now based on flow cytometry, is a little bit difficult for most clinical pathology laboratories. It requires immunofluorescent studies, typically down to levels of 1 in 10,000 cells.

But there are new techniques that are being developed where it should be possible to send off a sample like you would to a foundation medicine, for example, for MRD assessment down to levels of one in a million. So, when this happened and it's available to clinicians to assess for disease at the one-in-a-million level, it's clear to see that some of the patients that are reaching that level where you can't detect it may actually have a very long progression-free survival or may be cured, as Susan mentioned here. And that's quite exciting.

I think if you have a young patient who has certain features such as the expression mutated immunoglobulin genes, and they have good cytogenetics and they want to go forward to find a course of treatment and not have to deal with this disease day in and day out, which does cost time, I think it's a reasonable thing to consider. And the MRD assessment is very critical there. Because if you're able to show that the patient's achieved that level of response, it's quite clear the patient is going to enjoy a very prolonged progression-free survival. So, it's very useful to the patient.

Richard R. Furman, MD: One interesting piece of data that we will eventually have, coming out of Peter Hillmen's study looking at FCR versus IR, is modeling the time to MRD negativity. And also, how far down below MRD negativity do you need to go in order to be cured? We know that a large number of patients who are MRD-negative will still relapse. The question is: at what point is the immune system able to take over and suppress the CLL? Or at what point is it really zero? And so, hearing in this trial how the modeling works will give us a lot of information as to how to address what really would be an important endpoint.
Transcript Edited for Clarity

Transcript:

William G. Wierda, MD, PhD: What are your clinical objectives with chemo/chemoimmunotherapy? What are you trying to achieve today with standard of care, chemo/chemoimmunotherapy?

William G. Wierda, MD, PhD: And what I'm hearing is today chemo/chemoimmunotherapy is pretty much a standard of care for first-line. When we move into the discussion about the small molecule inhibitors, perhaps not so much anymore is chemoimmunotherapy a relevant issue.

Susan M. O’Brien, MD: Exactly.

Richard R. Furman, MD: But I think just to follow up on something that Susan had said: it's important to keep in mind that no one will ever argue that MRD negativity is certainly better than MRD positivity. It's unclear whether doing something additionally that makes one MRD-negative quicker really provides an advantage. And so certainly, if we identify patients who might not be served by a long time to MRD negativity, people with genomic instability—and this is where the complex karyotype really becomes very helpful—those are the people who you might justify getting a deep remission quickly. But by and large, you know progression-free survival is really going to be what's most important to patients. And so, whether or not you get there quickly or slowly, it's really, in essence, how are you going to do long term? And that's just an important thing to always keep in mind.

Susan M. O’Brien, MD: I think it is. And obviously, most of the MRD data that we have is, or all of it, is based on chemoimmunotherapy. On the other hand I'm willing to go out on a limb and say, whatever your treatment is, if you don't become MRD-negative, I don't buy that you're going to be in remission 10 years later. I don't think it's going to happen.

Richard R. Furman, MD: But we need to figure out with the novel agents when that time point is. The important question is, how do we assess? So we really need to reinvestigate all the prognostic markers with the new agents and figure out who is that subset of patients that is not going to be served with a novel agent. So when you look at the PCYC-1102 treatment-naïve population, all but one of those patients is doing remarkably well. The question is when you look at the relapsed/refractory patients and the number of people doing well is less, so we're down to about a 70% progression-free survival at three years.

Richard R. Furman, MD: Single-agent ibrutinib. It's really about identifying who are those 30% of patients and what else we can really do to help them long term.

William G. Wierda, MD, PhD: I think the nice thing about considering MRD and having a discussion about it is that it's potentially an early endpoint that we can look at, without having to wait for PFS, in order to develop new and more effective therapies. It's great that we have all these new very, very active agents and they have extended out the PFS curves, as you know, remarkably. But that's a challenge also in terms of developing new treatments and making advances. Because if all of our progress is dependent on looking at that endpoint, it's going to slow things down for us in terms of development.

Richard R. Furman, MD: Absolutely.

William G. Wierda, MD, PhD: It would be nice to have something that's an early endpoint to look at that will tell us, yes, this is an effective or a more effective treatment. And then we can move from there. What are your thoughts, Tom, on MRD and where it's potentially useful in the community and in research investigations?

Thomas J. Kipps, MD, PhD: I think the absence of minimal residual disease is very important, in that it's probably the only way you're going to be able to say that you can potentially cure a patient if they have no evidence of active disease. The technique for assessing for minimal residual disease, which is now based on flow cytometry, is a little bit difficult for most clinical pathology laboratories. It requires immunofluorescent studies, typically down to levels of 1 in 10,000 cells.

But there are new techniques that are being developed where it should be possible to send off a sample like you would to a foundation medicine, for example, for MRD assessment down to levels of one in a million. So, when this happened and it's available to clinicians to assess for disease at the one-in-a-million level, it's clear to see that some of the patients that are reaching that level where you can't detect it may actually have a very long progression-free survival or may be cured, as Susan mentioned here. And that's quite exciting.

I think if you have a young patient who has certain features such as the expression mutated immunoglobulin genes, and they have good cytogenetics and they want to go forward to find a course of treatment and not have to deal with this disease day in and day out, which does cost time, I think it's a reasonable thing to consider. And the MRD assessment is very critical there. Because if you're able to show that the patient's achieved that level of response, it's quite clear the patient is going to enjoy a very prolonged progression-free survival. So, it's very useful to the patient.

Richard R. Furman, MD: One interesting piece of data that we will eventually have, coming out of Peter Hillmen's study looking at FCR versus IR, is modeling the time to MRD negativity. And also, how far down below MRD negativity do you need to go in order to be cured? We know that a large number of patients who are MRD-negative will still relapse. The question is: at what point is the immune system able to take over and suppress the CLL? Or at what point is it really zero? And so, hearing in this trial how the modeling works will give us a lot of information as to how to address what really would be an important endpoint.
Transcript Edited for Clarity